Method of making dorzolamide hydrochloride

ABSTRACT

Processes for the preparation of dorzolamide hydrochloride and an intermediate of Formula IV, 
     
       
         
         
             
             
         
       
     
     are provided.

RELATED APPLICATIONS

The present application is a division of U.S. patent application Ser.No. 11/326,719, filed Jan. 6, 2006, which claims benefit of U.S.Provisional Patent Application No. 60/642,166, filed Jan. 6, 2005, thecontents of which are incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention is directed to methods of making dorzolamidehydrochloride.

BACKGROUND OF THE INVENTION

Dorzolamide hydrochloride, known chemically as5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxydehydrochloride, is a topically effective carbonic anhydrase inhibitoruseful in the treatment of ocular hypertension.

Dorzolamide hydrochloride has the structure of Formula I:

U.S. Pat. Nos. 4,677,155 and 4,797,413 disclose Dorzolamide. In theprior art synthesis of dorzolamide, a chiral hydroxysulfone is used as astarting material. The chiral hydroxysulfone starting material can beobtained using the processes disclosed in U.S. Pat. Nos. 5,157,129,5,474,919, and 5,760,249. In the disclosed processes, the chiralhydroxysulfone is obtained by the asymmetric enzymatic reduction of thecorresponding ketosulfone, or by cyclization of the chiral thienylthiobutyric acid, obtained, in turn, from a chiral hydroxyester orlactone, and the subsequent stereospecific reduction of the resultingketone.

Processes for the preparation of dorzolamide hydrochloride are describedin U.S. Pat. Nos. 4,797,413, 5,157,129, and 5,688,968 and in U.S. PatentApplication Publication No. 2003/0220509. The disclosed processesinvolve conversion of a hydroxysulfone to the correspondingacetamidosulfone by a Ritter reaction with retention of configuration,followed by introduction of a sulfonamido group, and the subsequentreduction of the amido group to an amine, providing the desired product.

The process disclosed in U.S. Pat. No. 4,797,413 includes activation ofthe 4-hydroxy group of the sulfonaminated hydroxysulfone with tosylchloride and the introduction of the desired alkylamino group bynucleophilic substitution, resulting in all diastereomeric products,which must be separated and resolved. As a result, at least 75 percentof the product is lost when the desired product is the more activeenantiomer.

There is a need in the art for a new process for the preparation ofDorzolamide and salts thereof.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a process forthe preparation of a protected derivative of Formula II, comprising:protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of Formula IV,

comprising: aminating the protected derivative of formula II with analkyl amine and an acid in the presence of a solvent selected from thegroup consisting of a polar aprotic organic solvent, water and a mixturethereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV, where Y is an organic or inorganic acidmoiety. Preferably Y is selected from the group consisting of aceticacid, fumaric acid, tartaric acid, sulfuric acid, hydrochloric acid, andhydrobromic acid. More preferably, the acid is HCl.

In another embodiment, the present invention is directed to a processfor preparing dorzolamide salt of formula I, where Y is as definedabove,

comprising: sulfonamidating of the compound of Formula IV by combiningthe compound of Formula IV with fuming sulfuric acid or chlorosulfonicacid, chlorinating the sulfonylated intermediate by the addition ofinorganic chlorinated agent, evaporating the inorganic chlorinated agentfrom the reaction mixture, adding a polar aprotic organic solvent,adding a base and afterwards adding an acid until dorzolamide saltcompound of Formula I is obtained.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by dissolving the dorzolamide salt in water,adding a base until a basic slurry is obtained, extracting the basicslurry with an aprotic polar organic solvent, which is immiscible inwater, until two phases are obtained, separating the organic phase,concentrating the organic phase to obtain a residue of dorzolamide base,and cooling the residue.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by combining dorzolamide base with an acidand with a polar aprotic organic solvent to obtain an acidic slurry,cooling the slurry to obtain a precipitate of dorzolamide salt, andrecovering the dorzolamide salt.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by dissolving the dorzolamide salt in water,adding a base until a basic slurry is obtained, extracting the basicslurry with an aprotic polar organic solvent, which is immiscible inwater, until two phases are obtained, separating the organic phase,concentrating the organic phase to obtain a residue of dorzolamide base,cooling the residue, combining the residue with an acid and with a polaraprotic organic solvent to obtain an acidic slurry, cooling the slurryto obtain a precipitate of dorzolamide salt, and recovering thedorzolamide salt.

In yet another embodiment, the present invention is directed to aprocess for the preparation of a dorzolamide salt of structural FormulaI, where Y is as defined above.

The process comprises:

(a) protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative;

(b) aminating the protected derivative of formula II with an alkyl amineand an acid in the presence of a solvent selected from the groupconsisting of a polar aprotic organic solvent, water and a mixturethereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV, where Y is as defined above;

and

(c) sulfonamidating of the compound of Formula IV by combining thecompound of Formula IV with fuming sulfuric acid or chlorosulfonic acid,chlorinating the sulfonylated intermediate by the addition of inorganicchlorinated agent, evaporating the inorganic chlorinated agent from thereaction mixture, adding a polar aprotic organic solvent, adding a base,and, afterwards, adding an acid until dorzolamide salt compound ofFormula I is obtained;

(d) purifying the dorzolamide salt compound of Formula I; and

(e) recovering the dorzolamide salt compound of Formula I.

In another embodiment, the present invention is directed to a processfor the preparation of a dorzolamide salt of structural Formula I, whereY is as defined above,

comprising obtaining a protected compound of formula II by the methoddescribed above and converting it to a compound of formula I.

In another embodiment, the present invention is directed to a processfor the preparation of a dorzolamide salt of structural Formula I, whereY is as defined above,

comprising obtaining a compound of formula IV by the method describedabove and converting it to a compound of formula I.

In yet another embodiment, the present invention is directed to aprocess for the preparation of a dorzolamide salt of structural FormulaI, where Y is as defined above,

Comprising: protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, adding an alkyl amine and an acid inthe presence of a solvent selected from the group consisting of a polaraprotic organic solvent, water and a mixture thereof, adding fumingsulfuric acid or chlorosulfonic acid, adding an inorganic chlorinatedagent, evaporating the inorganic chlorinated agent from the reactionmixture, adding a polar aprotic organic solvent, adding a base,afterwards adding an acid until dorzolamide salt compound of Formula Iis obtained, purifyng the dorzolamide salt compound of Formula I andrecovering the dorzolamide salt compound of Formula I.

In another embodiment, the present invention is directed to anintermediate of the dorzolamide salt having the formula (formula III):

In another embodiment, the present invention is directed to anintermediate of the dorzolamide hydrochloride having the formula(formula IV):

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the characteristic XRD pattern of the compound ofFormula IV.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “fuming sulfuric acid” refers to a sulfuricacid containing 10-25% free SO₃.

The present invention provides a process for the preparation ofdorzolamide and salts thereof that uses a chiral starting material, thusavoiding the need for an optical resolution process to obtain the finalproduct. The process includes transformation of one intermediate toanother in a process that is almost one pot, hence isolation of only oneintermediate is required. Moreover, the process can be adapted toindustrial scale.

In one embodiment, the present invention is directed to a process forthe preparation of a protected derivative of Formula II, comprising:protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative.

Preferably, the sulfonic acid derivative is arylsulfonyl oralkylsulfonyl chloride. More preferably, the arylsulfonyl chloride isbenzylsulfonyl chloride, tosyl chloride or toluenesulfonyl chloride.Most preferably, the arylsulfonyl chloride is benzylsulfonyl chloride.When the arylsulfonyl chloride is benzylsulfonyl, the obtained protectedcompound is a compound of Formula III.

Preferably, the process is performed at a temperature of up to about 0°C. More preferably, the process is performed at a temperature of fromabout −30° to about 0° C. for about 2 to about 4 hours. Preferably, theorganic base is selected from the group consisting of pyridine,triethylamine, and N,N-diisipropylethylamine. More preferably, theorganic base is triethylamine. Preferably, the polar aprotic organicsolvent is selected from the group consisting of acetone, dioxane,acetonitrile, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran,and pyridine. More preferably, the polar aprotic organic solvent istetrahydrofuran or ethyl acetate. After the addition of the base, thesulfonic acid derivative, and the polar aprotic organic solvent, thereaction mixture is stirred and triethylamine HCl salt may be obtained.Preferably, the obtained triethylamine HCl salt is filtered. Followingfiltration, the protected compound is preferably used in the next stepof the synthesis without further processing.

In another embodiment, the present invention is directed to a processfor the preparation of a compound of Formula IV, where Y is as definedabove,

comprising: aminating the protected derivative of formula II with analkyl amine and an acid in the presence of a solvent selected from thegroup consisting of a polar aprotic organic solvent, water and a mixturethereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV.

Preferably, the amination is carried out at a temperature of about 20°C. to about 30° C. for about 16 hours to about 20 hours. Preferably, thealkyl amine is ethyl amine. Preferably, the acid is an organic acid oran inorganic acid. Preferably, the organic acid is selected from thegroup consisting of acetic acid, fumaric acid, and tartaric acid.Preferably, the inorganic acid is selected from the group consisting ofsulfuric acid, hydrochloric acid, and hydrobromic acid. More preferably,the inorganic acid is HCl. Preferably, the polar aprotic organic solventis selected from the group consisting of acetone, dioxane, acetonitrile,tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, and pyridine.More preferably, the polar aprotic organic solvent is tetrahydrofuran orethyl acetate. Preferably, the acid is added until a pH of about 2 toabout 2.5 is obtained. Preferably, the acid is added to the solutionformed with alkyl amine and the solvent. Preferably, the solution isheated to a temperature of about 40° C. prior to the addition of HCl.Preferably, the solvent is removed from the reaction mixture.Preferably, the reaction mixture, containing alkyl amine, an acid and asolvent, is cooled to a temperature of about −15° C. to about 10° C.,more preferably, to a temperature of about −8° C.

In another embodiment, the present invention is directed to a processfor preparing dorzolamide salt of Formula I, where Y is as defined above

comprising: sulfonamidating of the compound of Formula IV by combiningthe compound of Formula IV with fuming sulfuric acid or chlorosulfonicacid, chlorinating the sulfonylated intermediate by the addition ofinorganic chlorinated agent, evaporating the inorganic chlorinated agentfrom the reaction mixture, adding a polar aprotic organic solvent,adding a base and afterwards adding an acid until the dorzolamide saltcompound of Formula I is obtained.

Preferably, the compound of Formula IV undergoes sulfonylation at atemperature of about −10° C. to about 25° C. for about 2 to about 24hours. Preferably, the resulting sulfonylated intermediate is notisolated, but is used directly in the next stage of step, whichcomprises chlorination of the sulfonylated intermediate by the additionof inorganic chlorinated agent at a temperature of from about −10° toabout 25° C. Preferably, the inorganic chlorinated agent is selectedfrom the group consisting of thionyl chloride, SO₂Cl₂, PCl₃, and POCl₃.The sulfonylated intermediate can be isolated by addition of an alcohol,such as n-butanol, and then reacted with an inorganic chlorinated agent.Preferably, after the addition of the inorganic chlorinated agent, thereaction mixture is heated to a temperature of about 60° C. to about 65°C. Preferably, after the chlorination is completed, the excess ofinorganic chlorinated agent is removed from the reaction mixture,preferably, by evaporation. Preferably, a residue is obtained after theevaporation. Preferably, after the evaporation of the inorganicchlorinated agent, a residue or diluted residue is obtained. Preferably,the polar aprotic organic solvent is selected from the group consistingof acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,2-methyltetrahydrofuran, and pyridine. More preferably, the polaraprotic organic solvent is tetrahydrofuran or ethyl acetate. Preferably,the base is added at a temperature of about −15° C. to about 30° C.Preferably, the residue or diluted residue is added to the base.Preferably, the base is an organic base or an inorganic base.Preferably, the organic base is ammonia. Preferably, the ammonia is anaqueous ammonia. Preferably, the inorganic base is selected from thegroup consisting of NaOH, KOH, K₂CO₃, and Na₂CO₃. Preferably, theorganic solvent is removed from the reaction mixture. Optionally, theacid is added in an alcohol such as ethanol. Preferably, the dorzolamidesalt is dorzolamide HCl.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by dissolving the dorzolamide salt in water,adding a base until a basic slurry is obtained, extracting the basicslurry with an aprotic polar organic solvent, which is immiscible inwater, until two phases are obtained, separating the organic phase,concentrating the organic phase to obtain a residue of dorzolamide base,and cooling the residue.

Preferably, the dorzolamide hydrochloride is dissolved in water at atemperature of about 20° C. to about 25° C. Preferably, the base is anorganic base or an inorganic base. Preferably, the organic base isammonia. Preferably, the ammonia is an aqueous ammonia. Preferably, theinorganic base is selected from the group consisting of NaOH, KOH,K₂CO₃, and Na₂CO₃. Preferably, the base is added until a pH of about 8.0to about 8.5 is obtained. Preferably, the aprotic polar organic solvent,which is immiscible in water, is selected from the group consisting ofisobutyl acetate, ethyl acetate, and dichloromethane. More preferably,the aprotic polar organic solvent, which is immiscible in water, isethyl acetate. Optionally, the concentration continuous until a drydorzolamide base is obtained. Optionally, the concentration continuousuntil a diluted dorzolamide base is obtained. Preferably, the residue iscooled to a temperature of about 10° C. to about 30° C., morepreferably, to a temperature of about 20° C. to about 25° C.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by combining dorzolamide base with an acidand with a polar aprotic organic solvent to obtain an acidic slurry,cooling the slurry to obtain a precipitate of dorzolamide salt, andrecovering the dorzolamide salt.

Preferably, the acid is an organic acid or an inorganic acid.Preferably, the organic acid is selected from the group consisting ofacetic acid, fumaric acid, and tartaric acid. Preferably, the inorganicacid is selected from the group consisting of sulfuric acid,hydrochloric acid, and hydrobromic acid. More preferably, the inorganicacid is HCl. Preferably, the slurry is cooled to a temperature of about0° C. to about 4° C. Preferably, the cooled slurry is stirred for aboutat least 4 hours, more preferably, for about 5 hours. Preferably, theacid is added in C₁ to C₄ alcohol. Preferably, the C₁ to C₄ alcohol isethanol. Preferably, after cooling the slurry, the slurry is filtereduntil obtaining a precipitate. Preferably, the precipitate is recoveredby washing it with a polar aprotic organic solvent, and drying it at atemperature of about 55° C. to about 60° C.

In another embodiment, the present invention is directed to a process ofpurifying dorzolamide salt by dissolving the dorzolamide salt in water,adding a base until a basic slurry is obtained, extracting the basicslurry with an aprotic polar organic solvent, which is immiscible inwater, until two phases are obtained, separating the organic phase,concentrating the organic phase to obtain a residue of dorzolamide base,cooling the residue, combining the residue with an acid and with a polaraprotic organic solvent to obtain an acidic slurry, cooling the slurryto obtain a precipitate of dorzolamide salt, and recovering thedorzolamide salt.

In yet another embodiment, the present invention is directed to aprocess for the preparation of a dorzolamide salt of structural FormulaI, where Y is as defined above,

The process comprises:

(a) protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative;

(b) aminating the protected derivative of formula II with an alkyl amineand an organic salt in the presence of a solvent selected from the groupconsisting of a polar aprotic organic solvent, water and a mixturethereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV, where Y is as defined above;

and

(c) sulfonamidating of the compound of Formula IV by combining thecompound of Formula IV with fuming sulfuric acid or chlorosulfonic acid,chlorinating the sulfonylated intermediate by the addition of inorganicchlorinated agent, evaporating the inorganic chlorinated agent from thereaction mixture, adding a polar aprotic organic solvent, adding a baseand afterwards adding an acid until dorzolamide salt compound of FormulaI is obtained;

(d) purifying the dorzolamide salt compound of Formula I; and

(e) recovering the dorzolamide salt compound of Formula I.

The preferred reaction of the compound of Formula II with the sulfonicacid derivative in step (a) provides a sulfonic acid protecting group.Preferably, sulfonic acid derivative is arylsulfonyl or alkylsulfonylchloride. More preferably, the arylsulfonyl chloride is benzylsulfonylchloride, tosyl chloride or toluenesulfonyl chloride. Most preferably,the arylsulfonyl chloride is benzylsulfonyl chloride. When thearylsulfonyl chloride is benzylsulfonyl, the obtained protected compoundis a compound of Formula III.

Step (a) is preferably performed at a temperature of up to about 0° C.More preferably, step (a) is performed at a temperature of from about−30° to about 0° C. for about 2 to about 4 hours. Preferably, theorganic base is selected from the group consisting of pyridine,triethylamine, and N,N-diisipropylethylamine. More preferably, theorganic base is triethylamine. Preferably, the polar aprotic organicsolvent is selected from the group consisting of acetone, dioxane,acetonitrile, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran,and pyridine. More preferably, the polar aprotic organic solvent istetrahydrofuran or ethyl acetate. After the addition of the base, thesulfonic acid derivative, and the polar aprotic organic solvent, thereaction mixture is stirred, and the triethylamine HCl salt may beobtained. Preferably, the obtained triethylamine HCl salt is filtered.Following filtration, the protected compound is preferably used in thenext step of the synthesis without further processing.

Preferably, the amination in step b) is carried out at a temperature ofabout 20° C. to about 30° C. for about 16 hours to about 20 hours.Preferably, the alkyl amine is ethyl amine. Preferably, the acid is anorganic acid or an inorganic acid. Preferably, the organic acid isselected from the group consisting of acetic acid, fumaric acid, andtartaric acid. Preferably, the inorganic acid is selected from the groupconsisting of sulfuric acid, hydrochloric acid, and hydrobromic acid.More preferably, the inorganic acid is HCl. Preferably, the polaraprotic organic solvent is selected from the group consisting ofacetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,2-methyltetrahydrofuran, and pyridine. More preferably, the polaraprotic organic solvent is tetrahydrofuran or ethyl acetate. Preferably,the acid is added until a pH of about 2 to about 2.5 is obtained.Preferably, the acid is added to the solution formed with alkyl amineand the solvent. Preferably, the solution is heated to a temperature ofabout 40° C. prior to the addition of HCl. Preferably, the solvent isremoved from the reaction mixture. Preferably, the reaction mixture,containing alkyl amine, an acid, and a solvent, is cooled to atemperature of about −15° C. to about 10° C., more preferably, to atemperature of about −8° C.

Preferably, in step (c), the compound of Formula IV undergoessulfonylation at a temperature of about −10° C. to about 25° C. forabout 2 to about 24 hours. Preferably, the resulting sulfonylatedintermediate is not isolated, but is used directly in the next stage ofstep, which comprises chlorination of the sulfonylated intermediate bythe addition of inorganic chlorinated agent at a temperature of fromabout −10° to about 25° C. Preferably, the inorganic chlorinated agentis selected from the group consisting of thionyl chloride, SO₂Cl₂, PCl₃,and POCl₃. The sulfonylated intermediate can be isolated by addition ofan alcohol, such as n-butanol, and then reacted with inorganicchlorinated agent. Preferably, after the addition of the inorganicchlorinated agent, the reaction mixture is heated to a temperature ofabout 60° C. to about 65° C. Preferably, after the chlorination iscompleted, the excess of inorganic chlorinated agent is removed from thereaction mixture, preferably, by evaporation. Preferably, a residue isobtained after the evaporation. Preferably, after the evaporation of theinorganic chlorinated agent, a residue or diluted residue is obtained.Preferably, the polar aprotic organic solvent is selected from the groupconsisting of acetone, dioxane, acetonitrile, tetrahydrofuran, ethylacetate, 2-methyltetrahydrofuran, and pyridine. More preferably, thepolar aprotic organic solvent is tetrahydrofuran or ethyl acetate.Preferably, the base is added at a temperature of about −15° C. to about30° C. Preferably, the residue or diluted residue is added to the base.Preferably, the base is an organic base or an inorganic base.Preferably, the organic base is ammonia. Preferably, the ammonia is anaqueous ammonia. Preferably, the inorganic base is selected from thegroup consisting of NaOH, KOH, K₂CO₃, and Na₂CO₃. Preferably, theorganic solvent is removed from the reaction mixture. Optionally, theacid is added in an alcohol such as ethanol. Preferably, the dorzolamidesalt is dorzolamide HCl.

The purification in step d) of the dorzolamide salt comprises:dissolving the dorzolamide salt in water, adding a base until a basicslurry is obtained, extracting the basic slurry with an aprotic polarorganic solvent, which is immiscible in water, until two phases areobtained, separating the organic phase, concentrating the organic phaseto obtain a residue of dorzolamide base, cooling the residue, combiningthe residue with an acid and with a polar aprotic organic solvent toobtain an acidic slurry, cooling the slurry to obtain a precipitate ofdorzolamide salt, and recovering the dorzolamide salt.

Optionally, the obtained dorzolamide salt may be purified bycrystallizing it from water or a mixture of isopropyl alcohol-methanol(as described in example 1).

In yet another embodiment, the present invention is directed to aprocess for the preparation of a dorzolamide salt of structural FormulaI, where Y is as defined above,

Comprising: protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, adding an alkyl amine and an acid inthe presence of a solvent selected from the group consisting of a polaraprotic organic solvent, water and a mixture thereof, adding fumingsulfuric acid or chlorosulfonic acid, adding an inorganic chlorinatedagent, evaporating the inorganic chlorinated agent from the reactionmixture, adding a polar aprotic organic solvent, adding a base,afterwards adding an acid until dorzolamide salt compound of Formula Iis obtained, purifying the dorzolamide salt compound of Formula I andrecovering the dorzolamide salt compound of Formula I.

The final purified dorzolamide hydrochloride prepared by this methoddoes not contain more than 0.1% by weight of the corresponding 4R,6Sdorzolamide.

In another embodiment, the present invention is directed to a processfor the preparation of a dorzolamide salt of structural Formula I, whereY is as defined above,

comprising obtaining a protected compound of formula II by the methoddescribed above and converting it to a compound of formula I.

In another embodiment, the present invention is directed to a processfor the preparation of a dorzolamide salt of structural Formula I, whereY is as defined above,

comprising obtaining a compound of formula IV by the method describedabove and converting it to a compound of formula I.

In another embodiment, the present invention is directed to anintermediate of the dorzolamide salt having the formula (formula III):

In another embodiment, the present invention is directed to anintermediate of the dorzolamide hydrochloride having the formula(formula IV):

The intermediate of formula IV may be further characterized by a powderXRD pattern with peaks at 9.6, 12.6, 16.4, 17.1, 19.1, 21.9, 25.3, 26.1,27.7 and 30.2±0.1 degrees 2θ, substantially as depicted in FIG. 1. Theintermediate of formula IV may be further characterized by a ¹H NMR(DMSO-d₆) with peaks at: δ 9.74 (m, 2H), 8.12 (d, 1H), 7.65 (d, 1H),4.68 (m, 1H), 4.20 (m, 1H), 3.16 (m, 1H), 3.05 (m, 1H), 2.78 (d, 1H),2.53 (m, 1H), 1.37 (t, 3H), and 1.30 (t, 3H). The intermediate offormula IV may be further characterized by a ¹³C NMR (DMSO-d₆) withpeaks at: δ 139.4, 138.5, 132.7, 129.7, 52.2, 50.0, 41.4, 31.8, 11.9,and 10.9. The intermediate of formula IV may be further characterized byMS: [M+H] of 246.06. The intermediate of formula IV may be furthercharacterized by an IR (KBr): μ (cm⁻¹) 3120, 3000-2850, 2800-2500, 1560,1540, 1522, 1300, 1264, 1140, 750, and 710.

The following non-limiting examples are merely illustrative of thepreferred embodiments of the present invention, and are not to beconstrued as limiting the invention, the scope of, which is defined bythe appended claims.

EXAMPLE 1

A compound of Formula IV,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide hydrochloride can be synthesized according to the followingscheme.

In the process of the invention, a solution of4-(R)-hydroxy-5,6-dihydro-6-(S)-methyl-4H-thieno[2,3-b]thiopyran-7,7-dioxide,i.e., a compound of Formula II, in THF is prepared by mixing 20 g, 91.6mmol, of the compound with 200 ml of anhydrous THF. The solution iscooled to about −20°±5° C. Triethylamine in an amount of 19.4 ml is thenadded gradually, while maintaining the temperature at −20°±3° C. Asolution of α-toluenesulfonylchloride in an amount of 21.62 g, 109.9mmol, in 66 ml of anhydrous THF is added in portions under an inertatmosphere, while maintaining the temperature at −18°±3° C. The reactionmixture is stirred for 2 to 2.5 hours, and the resulting triethylaminehydrochloride salt is filtered under an inert atmosphere. The cake iswashed with 40 ml of cooled THF, and the combined filtrate is usedimmediately without further processing in the next step of thesynthesis, according to the following scheme.

A 2 molar solution of ethylamine in THF in an amount of 674 ml is addedto a cold solution of the compound of Formula III prepared according tothe method discussed above in one portion at 0°±5° C. The resultingmixture is warmed to 25°±5° C., and aged for 16 to 20 hours. Afteraging, the mixture is cooled to −5°±5° C., and 300 ml of 4 molar aqueoushydrochloric acid is added to reduce the pH to about 2.5, whilemaintaining the temperature at −5°±5° C. The acidified reaction mixtureis then concentrated to remove THF, and 800 ml of ethyl acetate isadded. The resulting slurry is cooled to −7°±˜5° C. After stirring thesuspension at −7°±5° C. for 8 to 18 hours, the resulting solid isfiltered and dried at 50° C. under vacuum. The process has been shown toprovide a yield of a crude aminated intermediate of Formula IV of 70 to80 percent with a chromatographic purity of 98.5 to 99.5 percent.

The dorzolamide hydrochloride product is prepared from the aminatedintermediate of Formula IV by the following scheme.

The aminated intermediate of Formula IV, in an amount of 20 g, is addedin portions under an inert atmosphere to 40 ml of fuming sulfuric acidat room temperature. The reaction mixture is stirred for 2 to 3 hours at20°±5° C. Thionyl chloride in an amount of 160 ml is then added in oneportion, and the resulting mixture is refluxed for 3 to 6 hours. Excessthionyl chloride is evaporated, and the residue is stirred into amixture of aqueous ammonia and THF (300-300 ml) in portions, under aninert atmosphere, while maintaining the temperature at −5°±5° C.

After stirring the reaction mixture for 75±15 minutes, the resultingammonium sulfate is filtered. The cake is then washed with two 80 mlvolumes of THF, the filtrate is concentrated to remove THF, andextracted with four 300 ml volumes of ethyl acetate. The organic layersare combined, concentrated to 300 ml, and stirred well, as 16 ml ofconcentrated hydrochloric acid is added slowly. The slurry is stirredfor 40±15 minutes, filtered, and washed with two 40 ml volumes of ethylacetate. The resulting white solid is dried under vacuum at 50° C. Theprocess has been shown to provide a yield of crude dorzolamide HCl of 70to 75 percent. The crude salt is recrystallized from water or a mixtureof isopropyl alcohol-methanol. The amount of the 4R,6S dorzolamide (atRRt 1.09) is lower than 0.1 percent.

The sulfonylated intermediate is isolated as follows: The aminatedintermediate of Formula IV, in an amount of 2 g, is added in portionsunder an inert atmosphere to 4 ml of fuming sulfuric acid at roomtemperature. The reaction mixture is stirred for 2 to 3 hours at 20°±5°C. then stirred into 240 ml of n-butanol. After stirring the suspensionat −7°±5° C. for 8-18 hours, the resulting solid is filtered, washedwith n-butanol, and dried at 50° C. under vacuum to give 1.80 g of thedesired product in 80 percent yield. This material can be transformed tothe final dorzolamide hydrochloride.

EXAMPLE 2 Preparation of5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide Hydrochloride Salt (Formula IV)

Tetrahydrofuran (50 l) and triethyl amine (4.8 l) are added to4-(R)-hydroxy-5,6-dihydro-6-(S)-methyl-4H-thieno[2,3b]thiopyran-7,7-dioxide (5 Kg) and stirred under a nitrogen atmosphereat room temperature. The solution is cooled to −10° C. Benzylsulfonylchloride (5.4 Kg) solved in THF (15 l) is added to the DRZ-19 THFsolution in portions while maintaining the temperature below 0° C. Thefeeding funnel is washed with THF (2 l). The reaction mixture is stirredat 0° C. for 2-4 hours. The formed TEA HCl is filtered and the cake iswashed with THF (2×10 l) Ethylamine in THF (30%, 63.7 l) is added to thefiltrate and the reaction mixture is stirred at 20°-25° C. for 16 hours.Ethylamine gas prepared by heating of 70% EtNH₂ water solution (50 l) isabsorbed in cooled THF (30 l). Water (20 l) is added to the reactionmixture and THF is evaporated from the filtrate at 40°±5° C. undervacuum. The residue is cooled to 20°-25° C., ethyl acetate (60 l) isadded to it and stirred vigorously. After phase separation, the organicphase is washed with water (20 l). The ethyl acetate phase is heated to40°±2° C. and hydrochloric acid (4M, ˜8-10 l) is added to it duringstirring to set pH 2.0-2.5. The formed slurry is cooled to −8°±2° C. andstirred for 3 hours at this temperature. The slurry is filtered, theprecipitated HCl salt is washed with ethyl acetate (30 l) and dried at55°-60° C. under vacuum for 4-8 hours to give the desired salt (˜5 Kg).

Preparation of Dorzolamide Hydrochloride Product from the AminatedIntermediate of Formula IV

Fuming sulfuric acid (20%, 5 l) is cooled to −7°±2° C. and the aminatedintermediate of Formula IV (2.5 Kg) is added to it in portions duringstirring. The temperature of the reaction mixture is increased to 20°±5°C. during addition of the aminated intermediate of Formula IV. Thereaction mixture is stirred for 22 hours at 20°±5° C. Thionyl chloride(20 l) is added to the stirred reaction mixture at 20±5° C. The reactionmixture is heated to 60°-65° C. and stirred for 24 hours at thistemperature. The mixture is cooled back to 40±2° C. and the excessamount of thionyl chloride is evaporated at this temperature undervacuum. (The volume of the residue: ˜9 l.) The residue is cooled to−5°±2° C.

Ethyl acetate (75 l) is cooled to −10°±5° C. and the residue is added toit at this temperature. The temperature of the diluted solution: 10°-25°C. Aqueous ammonia (25%, 75 l) is cooled to −10°±5° C. and the residueis added to it at this temperature during effective stirring, whilemaintaining the temperature below 30° C.

The final pH: ˜11. The slurry is cooled to 0°±2° C. and stirred for 14hours at this temperature. The formed ammonium sulfate is filtered andthe cake is washed with ethyl acetate (2×20 l and 10 l). Ethyl acetateis evaporated from the filtrate at 38°±2° C. under vacuum. The residueis heated to 38°±2° C., washed with toluene (3×37.5 l) at thistemperature. Water (25 l) is added to the aqueous phase, cooled to20°-25° C., and extracted with ethyl acetate (3×75 l, 37.5 l, and 37.5l). The collected ethyl acetate phase is concentrated to ˜100 l at38°±2° C. under vacuum. The residue is cooled to 20°-25° C. and hydrogenchloride in ethanol (5%, 10.8 l) is added to it during stirring. Theformed slurry is stirred for 1 hour at 20°-25° C. then cooled to 0°-4°C. and stirred for 5 hours at this temperature. The slurry is filtered,the precipitated HCl salt is washed with ethyl acetate (2×20 l) anddried at 55°-60° C. under vacuum for 4-8 hours to give Dorzolamidehydrochloride salt (˜2 Kg).

Crude Dorzolamide hydrochloride salt (9 Kg) is solved in water (225 l)at 20°-25° C. and the pH is set to 8.0-8.5 by addition of 25% of aqueousammonia (2 l). The formed slurry is extracted with ethyl acetate (5×72l). The collected ethyl acetate phase is concentrated to 180 l by vacuumdistillation. The residue is cooled to 20°-25° C., ethyl acetate (45 l)and hydrogen chloride in ethanol (5%, 22.5 l) are added to it duringstirring (pH: ˜1.0). The formed slurry is stirred for 1 hour at 20°-25°C. then cooled to 0°-4° C. and stirred for 5 hours at this temperature.The slurry is filtered, the precipitated HCl salt is washed with ethylacetate (2×30 l), and dried at 55°-60° C. under vacuum for 4-8 hours togive purified Dorzolamide hydrochloride salt (˜8.2 Kg).

Purified Dorzolamide hydrochloride salt (8 Kg) dissolved in water (24 l)at 95°-105° C. and treated with active carbon (80 g). After filtration,the water solution is cooled gradually to 0°-4° C. and stirred for 3-5hours at this temperature. The slurry is filtered, the precipitated HClsalt is washed with cooled water (2×5 l) and dried at 55°-60° C. undervacuum for 4-8 hours to give crystallized DRZ HCl salt (˜6.6 Kg).

While it is apparent that the invention disclosed herein is wellcalculated to fulfill the objects stated above, it will be appreciatedthat numerous modifications and embodiments can be devised by thoseskilled in the art. Therefore, it is intended that the appended claimscover all such modifications and embodiments as falling within the truespirit and scope of the present invention.

1. A process for the preparation of a protected compound, comprising:protecting the hydroxy group of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative of thecompound of Formula II.
 2. The process of claim 1, wherein the sulfonicacid derivative is arylsulfonyl or alkylsulfonyl chloride.
 3. Theprocess of claim 2, wherein the arylsulfonyl chloride is benzylsulfonylchloride, tosyl chloride or toluenesulfonyl chloride.
 4. The process ofclaim 3, wherein the arylsulfonyl chloride is benzylsulfonyl chloride.5. The process of claim 1, wherein the process is performed at atemperature of up to about 0° C.
 6. The process of claim 5, wherein theprocess is performed at a temperature of from about −30° to about 0° C.7. The process of claim 1, wherein the organic base is selected from thegroup consisting of pyridine, triethylamine, andN,N-diisipropylethylamine.
 8. The process of claim 7, wherein theorganic base is triethylamine.
 9. The process of claim 1, wherein thepolar aprotic organic solvent is selected from the group consisting ofacetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,2-methyltetrahydrofuran, and pyridine.
 10. The process of claim 9,wherein the polar aprotic organic solvent is tetrahydrofuran or ethylacetate.
 11. A process for the preparation of a compound of Formula IV

comprising: aminating a protected derivative of formula II, wherein Y isan acid moiety, with an alkyl amine and an acid in the presence of asolvent selected from the group consisting of a polar aprotic organicsolvent, water and a mixture thereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV.
 12. The process of claim 11, wherein theamination is carried out at a temperature of about 20° C. to about 30°C.
 13. The process of claim 11, wherein the amination is carried out forabout 16 hours to about 20 hours.
 14. The process of claim 11, whereinthe alkyl amine is ethyl amine.
 15. The process of claim 11, wherein theacid is an organic acid or an inorganic acid.
 16. The process of claim15, wherein the organic acid is selected from the group consisting ofacetic acid, fumaric acid, and tartaric acid.
 17. The process of claim15, wherein the inorganic acid is selected from the group consisting ofsulfuric acid, hydrochloric acid, and hydrobromic acid.
 18. The processof claim 17, wherein the inorganic acid is hydrochloric acid.
 19. Theprocess of claim 11, wherein the polar aprotic organic solvent isselected from the group consisting of acetone, dioxane, acetonitrile,tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, and pyridine.20. The process of claim 19, wherein the polar aprotic organic solventis tetrahydrofuran or ethyl acetate.
 21. A process for preparingdorzolamide salt of formula I

comprising: sulfonamidating of the compound of Formula IV, wherein Y isan acid moiety, by combining the compound of Formula IV with fumingsulfuric acid or chlorosulfonic acid, chlorinating the sulfonylatedintermediate by the addition of inorganic chlorinated agent, evaporatingthe unreacted inorganic chlorinated agent from the reaction mixture,adding a polar aprotic organic solvent, adding a base and afterwardsadding an acid corresponding to Y until dorzolamide salt compound ofFormula I is obtained.
 22. The process of claim 21, wherein thesulfonylation is at a temperature of about −10° C. to about 25° C. 23.The process of claim 21, wherein the sulfonylation is for about 2 toabout 24 hours.
 24. The process of claim 21, wherein the inorganicchlorinated agent is selected from the group consisting of thionylchloride, SO₂Cl₂, PCl₃, and POC
 3. 25. The process of claim 21, whereinthe inorganic chlorinated agent is added at a temperature of from about−10° to about 25° C.
 26. The process of claim 21, wherein after theaddition of the inorganic chlorinated agent, the reaction mixture isheated to a temperature of about 60° C. to about 65° C.
 27. The processof claim 21, wherein the polar aprotic organic solvent is selected fromthe group consisting of acetone, dioxane, acetonitrile, tetrahydrofuran,ethyl acetate, 2-methyltetrahydrofuran, and pyridine.
 28. The process ofclaim 27, wherein the polar aprotic organic solvent is tetrahydrofuranor ethyl acetate.
 29. The process of claim 21, wherein the base is anorganic base or an inorganic base.
 30. The process of claim 29, whereinorganic base is ammonia.
 31. The process of claim 29, wherein theinorganic base is selected from the group consisting of NaOH, KOH,K₂CO₃, and Na₂CO₃.
 32. The process of claim 21, wherein the base isadded at a temperature of about −15° C. to about 30° C.
 33. The processof claim 21, wherein after the addition of the polar aprotic organicsolvent, the reaction mixture is added to the base.
 34. The process ofclaim 21, wherein the dorzolamide salt compound of Formula I isdorzolamide HCl, of Formula I,


35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled) 39.(canceled)
 40. (canceled)
 41. (canceled)
 42. (canceled)
 43. (canceled)44. (canceled)
 45. (canceled)
 46. (canceled)
 47. (canceled) 48.(canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled)
 52. (canceled)53. A process for the preparation of dorzolamide salt of structuralFormula I,

wherein Y is an acid moiety, comprising: (a) protecting the hydroxygroup of5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide, having the structural Formula II

with a sulfonic acid derivative, in the presence of an organic base anda polar aprotic organic solvent, to obtain a protected derivative; (b)aminating the protected derivative of formula II with an alkyl amine andan organic salt in the presence of a solvent selected from the groupconsisting of a polar aprotic organic solvent, water and a mixturethereof, to give5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-[2,3-b]thiopyran7,7-dioxide salt of Formula IV;

and (c) sulfonamidating of the compound of Formula IV by combining thecompound of Formula IV with fuming sulfuric acid or chlorosulfonic acid,chlorinating the sulfonylated intermediate by the addition of inorganicchlorinated agent, evaporating the inorganic chlorinated agent from thereaction mixture, adding a polar aprotic organic solvent, adding a baseand afterwards adding an acid until dorzolamide salt compound of FormulaI is obtained; (d) purifying the dorzolamide salt compound of Formula I;and (e) recovering the dorzolamide salt compound of Formula I.
 54. Theprocess of claim 53, wherein the sulfonic acid derivative in step (a) isarylsulfonyl or alkylsulfonyl chloride.
 55. The process of claim 54,wherein the arylsulfonyl chloride is benzylsulfonyl chloride, tosylchloride or toluenesulfonyl chloride.
 56. The process of claim 55,wherein the arylsulfonyl chloride is benzylsulfonyl chloride.
 57. Theprocess of claim 53, wherein step (a) is performed at a temperature ofup to about 0° C.
 58. The process of claim 57, wherein step (a) isperformed at a temperature of from about −30° to about 0° C.
 59. Theprocess of claim 53, wherein the base in step (a) is selected from thegroup consisting of pyridine, triethylamine, andN,N-diisipropylethylamine.
 60. The process of claim 53, wherein the basein step (a) is triethylamine.
 61. The process of claim 53, wherein thepolar aprotic organic solvent in step (a) is selected from the groupconsisting of acetone, dioxane, acetonitrile, tetrahydrofuran, ethylacetate, 2-methyltetrahydrofuran, and pyridine.
 62. The process of claim61, wherein the polar aprotic organic solvent tetrahydrofuran or ethylacetate.
 63. The process of claim 53, wherein the amination in step (b)is carried out at a temperature of about 20° C. to about 30° C.
 64. Theprocess of claim 53, wherein the amination in step (b) is carried outfor about 16 hours to about 20 hours.
 65. The process of claim 53,wherein the alkyl amine in step (b) is ethyl amine.
 66. The process ofclaim 53, wherein the acid in step (b) is an organic acid or aninorganic acid.
 67. The process of claim 66, wherein the organic acid isselected from the group consisting of acetic acid, fumaric acid, andtartaric acid.
 68. The process of claim 66, wherein the inorganic acidis selected from the group consisting of sulfuric acid, hydrochloricacid, and hydrobromic acid.
 69. The process of claim 68, wherein theinorganic acid is HCl.
 70. The process of claim 53, wherein the polaraprotic organic solvent in step b) is selected from the group consistingof acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,2-methyltetrahydrofuran, and pyridine.
 71. The process of claim 70,wherein the polar aprotic organic solvent is tetrahydrofuran or ethylacetate.
 72. The process of claim 53, wherein the compound of Formula IVin step (c) undergoes sulfonylation at a temperature of about −10° C. toabout 25° C.
 73. The process of claim 53, wherein the sulfonylation instep (c) is for about 2 to about 24 hours.
 74. The process of claim 53,wherein the chlorination in step (c) is at a temperature of from about−10° to about 25° C.
 75. The process of claim 53, wherein the inorganicchlorinated agent in step (c) is selected from the group consisting ofthionyl chloride, SO₂Cl₂, PCl₃, and POCl₃.
 76. The process of claim 53,wherein after the addition of the inorganic chlorinated agent in stepc), the reaction mixture is heated to a temperature of about 60° C. toabout 65° C.
 77. The process of claim 53, wherein the polar aproticorganic solvent in step (c) is selected from the group consisting ofacetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,2-methyltetrahydrofuran, and pyridine.
 78. The process of claim 77,wherein the polar aprotic organic solvent is tetrahydrofuran or ethylacetate.
 79. The process of claim 53, wherein the base in step (c) is anorganic base or an inorganic base.
 80. The process of claim 79, whereinthe organic base is ammonia.
 81. The process of claim 79, wherein theinorganic base is selected from the group consisting of NaOH, KOH,K₂CO₃, and Na₂CO₃.
 82. The process of claim 51, wherein the base in step(c) is added at a temperature of about −15° C. to about 30° C.
 83. Theprocess of claim 53, wherein after the addition of the polar aproticorganic solvent, the reaction mixture is added to the base.
 84. Theprocess of claim 53, wherein the purification in step (d) of thedorzolamide salt comprises: dissolving the dorzolamide salt in water,adding a base until a basic slurry is obtained, extracting the basicslurry with aprotic polar organic solvent, which is immiscible in water,until two phases are obtained, separating the organic phase,concentrating the organic phase to obtain a residue of dorzolamide base,cooling the residue, combining the residue with an acid and with a polaraprotic organic solvent to obtain an acidic slurry, cooling the slurryto obtain a precipitate of dorzolamide salt, and recovering thedorzolamide salt.
 85. (canceled)


86. The process of claim 1, further comprising converting the protectedcompound of formula II to a compound of formula I.
 87. The process ofclaim 11, further comprising converting the compound of formula IV to acompound of formula I.